Question

a. Why are fluorinated bases readily incorporated during DNA synthesis? b. Draw a fluorinated thymidine analog-adenine base pair and label the \(\mathrm{C} 1^{\prime}-\mathrm{C} 1^{\prime}\) distance and angles between the 1'- \(^{\prime}-1^{\prime}\) vector and the glycosyl bonds with predicted values.

Short answer

Fluorinated bases mimic natural bases and maintain DNA stability. See drawn FdU-A with labeled structures.

Step-by-step solution

Understand Fluorinated Base Incorporation

Fluorinated bases are incorporated during DNA synthesis because they closely resemble natural bases in shape and size, enabling them to pair with complementary bases in the DNA strand. The presence of fluorine can enhance base-pairing stability and mimic natural hydrogen bonding.

Identify the Fluorinated Thymidine Analog

A commonly used fluorinated thymidine analog is 5-fluoro-2'-deoxyuridine (FdU), where the methyl group of thymidine is replaced by a fluorine atom. This small change makes it similar enough to be incorporated in DNA.

Draw the Thymidine-Adenine Base Pair

Draw the structure of the 5-fluoro-2'-deoxyuridine (thymidine analog) paired with adenine, maintaining the standard Watson-Crick base pairing. The fluorine atom should be indicated on the thymidine analog where the methyl group is typically positioned.

Identify the Locations of C1' Atoms

Label the C1' atoms on both the deoxyribose sugar of thymidine and adenine. In a DNA strand, each base is linked to a deoxyribose sugar.

Measure C1'-C1' Distance and Angles

The C1'-C1' distance typically measures around 10.4 Å in a typical Watson-Crick base pair. The angles between the C1'-C1' vector and each glycosyl bond are roughly 55° due to the orientation of the base pairing.

Key concepts

Fluorinated Bases

Fluorinated bases are derivatives of the natural nucleobases where one or more hydrogen atoms are replaced by fluorine. This substitution is crucial because fluorine has properties similar to a hydrogen atom—it is small in size—and can form strong bonds due to its electronegativity. This resemblance to natural bases helps fluorinated bases fit precisely into the DNA structure during DNA synthesis.

Here is why they are used:

• Increased Stability: Fluorine enhances the stability of base pairing. It can mimic the effects of natural hydrogen bonds, contributing to a more stable, sometimes even more resistant DNA strand.
• Therapeutic Applications: In cancer treatment and viral infections, fluorinated bases can disrupt DNA replication of malignant cells, making them a potent therapeutic tool.
• Molecular Similarity: The similarity in size and shape to natural bases allows them to integrate seamlessly into a growing DNA strand, ensuring effective pairing with complementary bases.

Watson-Crick Base Pairing

Watson-Crick base pairing is the fundamental principle behind DNA's double helix structure where guanine pairs with cytosine, and adenine pairs with thymine in DNA. These pairings are mediated by hydrogen bonds that stabilize the DNA structure.

Here's what happens during the pairing process:

• Specificity: Each nucleotide on one strand pairs with a specific counterpart on the opposite strand, driven by hydrogen bonding; A with T (or U in RNA), and G with C.
• Geometry: The pairs have shapes that fit perfectly, similar to puzzle pieces, maintaining the uniform distance between the two strands of the DNA helix.
• Functional Role: This specific pairing enables the accurate replication of DNA during cell division, ensuring genetic information is preserved.
• Role of Modifications: Alterations like the introduction of fluorinated bases do not disrupt this pairing rule. The geometry and ability to form hydrogen bonds remain intact, even with the presence of fluorine instead of a methyl group in the base structure.

C1'-C1' Distance

The \(\text{C1'-C1'}\) distance is a specific measurement between the C1' atoms on the sugars of two nucleotides that form a base pair. Understanding this distance is crucial for comprehending the molecular alignment of DNA.

Key aspects of this measurement:

• Measurement: Normally, this distance measures approximately 10.4 Å in Watson-Crick base pairs. This standard distance is necessary to maintain the uniform double helical structure of DNA.
• Structural Importance: The consistent \(\text{C1'-C1'}\) distance ensures that DNA strands run parallel creating stability and efficiency in replication and transcription processes.
• Impact of Alterations: The introduction of modifications like fluorinated bases does not significantly change the \(\text{C1'-C1'}\) distance, allowing for successful DNA synthesis despite molecular adjustments. The angles in the base pair also maintain a standard measure of around 55°, aligning the complementary bases optimally.

These parameters support the structural integrity and function of DNA, which is crucial for the effective storage and transmission of genetic information.